Project Summary/Abstract This is an application for a K01 award for Dr. Adrian Oblak, an Assistant Research Professor at Indiana University School of Medicine, Department of Pathology and Laboratory Medicine. Dr. Oblak is establishing herself as an independent researcher studying the molecular mechanisms leading to neurodegenerative diseases. This K01 award will provide Dr. Oblak with the financial support, training and mentorship to accomplish the following goals in order to develop her career in neurodegenerative disease research: (1) to design, create, and utilize a Mapt mouse model to determine the effects of the loss of Mapt expression in the adult mouse; (2) to become proficient in the use of stereotaxic methods to deliver tau preparations to the entorhinal cortex; (3) to gain experience in the neuropathologic evaluation of samples from patients and mouse models with neurodegeneration; (4) to obtain training in molecular biology, biochemistry and molecular genetics to enhance and compliment Dr. Oblak?s neuroanatomy background, thus broadening her range and ability to study neurodegeneration and (5) to develop an independent research career with the help of successful mentors and the development of healthy and productive collaborations. To achieve these goals, Dr. Oblak has developed a mentoring team which includes two mentors: Drs. Bernardino Ghetti (a world-renowned leader in neurodegenerative diseases; primary mentor) and Ruben Vidal (a molecular biologist and biochemist with expertise in the development and study of animal models for neurodegenerative diseases; co-mentor), as well as a supportive team of collaborators composed of Dr. Mary Guerriero-Austrom (psychologist, Director of Faculty Development, Director of Outreach, Recruitment and Education Core, Indiana Alzheimer Disease Center), Dr. Bruce Lamb, Executive Director, Stark Neuroscience Center and Dr. Michel Goedert, a world renowned expert in tau research and Joint Head of the Division of Neurobiology at the MRC Laboratory of Molecular Biology, Cambridge, UK, Dr. Su Gao, Professor of Biostatistics Indiana University School of Medicine, Dr. Martin Farlow, Professor of Neurology and Dr. Liana Apostolova, Professor of Neurology. Dr. Oblak?s proposed research focuses on the effects of decreasing tau expression during the progression of tauopathies. Tau has recently become a prominent target for the development of therapeutic interventions for preventing or delaying the progression of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD) and some forms of prion diseases. To determine if decreasing Mapt expression can slow or prevent progression of tau pathology, and to uncover the consequences of modulating Mapt expression in adult tissue, the following specific aims will be performed: Specific Aim 1. To generate a mouse model in which expression of Mapt can be conditionally knocked out (cKO). We will use specific promoters driving expression of an inducible form of Cre (CreERT2) to induce recombination of Mapt in specific cell types (neurons and glia) of the central nervous system (CNS). This approach will allow us to study the consequence of loss of tau expression in adult mice, and thus avoiding developmental compensatory effects observed in classical tau knockout (Mapt-/-) mice. Specific Aim 2. To test in vivo whether neuronal (or glial) tau expression is needed for the spreading of abnormal tau to brain regions in a prion-like manner. To complete this goal, we will evaluate and compare tau deposition following targeted stereotaxic injections of human tauopathy brain extracts into the brains of Mapt cKO mice. TMX induction of recombination will be performed prior to (Aim 2a) or following (Aim 2b) inoculation with the tau inocula. The ultimate goal of this project is to determine if targeting the expression of Mapt will be an effective therapeutic target to control the progression and/or propagation of tauopathy. Current research suggests that tau propagation through the brain occurs in a prion like manner. In addition, these studies will determine which cell populations in the CNS are contributing the most to tau propagation and will be the most effective target. This work is innovative because it will look at the effects of modulating tau expression in defined cell populations and the effects on the development and progression of induced tau pathology in vivo using endogenous tau gene expression. Findings of this proposed research are expected to make a significant contribution to our understanding of Mapt expression in the pathogenesis of tauopathy and whether regulating Mapt expressing cells could be used as a potential therapeutic approach.